The International Consortium on Innovation and Quality in Pharmaceutical Development (IQ) formed in 2010 is an association of over 25 pharmaceutical and biotechnology companies with a mission to advance science-based and scientifically-driven standards and regulations for medicinal products worldwide. In the June 2012 issue of Pharmaceutical Technology, a paper was provided which described the IQs Good Manufacturing Practices (GMPs) in Early Development working group (1). This working group (WG) is focused on developing recommended approaches to applying GMPs in several areas of Early Phase CMC development activities (e.g., Phase 1 to Phase 2a). A key premise of the GMPs in Early Development WG is that existing GMP guidance documents for early development are vague and that improved clarity with options to meet GMP expectations would be helpful. Although more prescriptive guidance is not advocated, the sharing of best practices in this paper is done herein to advance innovation in drug product development by improving cycle times, while maintaining appropriate product quality and ensuring patient safety.

A consequence of the absence of clarity surrounding early phase GMP guidance has been varied interpretation and application of existing GMP guidance within different companies and regulatory bodies according to their own culture and risk tolerance. Internal debates often result in conservative "one-size-fits-all" interpretations that rely on International Conference on Harmonization (ICH) guidelines that are relevant to commercial product development and do not distinguish differences in practices between early development and later-stage development (i.e., Phase 2b and beyond). A key driver of the IQ WG, therefore, has been to collectively define the minimum acceptable practices within industry regarding GMP expectations in early development that allow for added flexibility and that are consistent with existing guidance and statutes (2, 3).

As outlined in the introductory paper to this series, the efforts of the GMPs in Early Development WG have been focused into the following four areas of Chemistry, Manufacturing, and Controls (CMC) activities: Analytical Method Validation, Specifications, Drug Product Manufacturing, and Stability (1). The initial scope of these efforts has been limited to small-molecule development, which support First in Human (FIH) through Phase 2a (proof-of-concept) clinical studies.

A series of whitepapers describing a recommended approach to applying GMPs in each of these areas is being published within this journal. In past editions, approaches to Analytical Method Validation, and Manufacturing to support health authority submissions were provided (4, 5); approaches to Specification setting will be published in the October 2012 issue of Pharmaceutical Technology.

In this paper, Part IV, stability needs are discussed. During early drug development, stability data can be generated to support the manufacture and storage of clinical products to meet regulatory expectations for Investigational New Drug (IND), Investigational Medicinal Product Dossier (IMPD), or Clinical Trial Application (CTA) filings and to help understand the product and process. The authors illustrate some best practices for stability to support early phase clinical trials in this paper; however, some companies may choose to do more, or possibly less, at their discretion and with appropriate science- and risk-based justifications suitable for the phases and purposes of development. The GMP quality systems (e.g., chamber qualification, standard operating procedures) used to support such studies are not the focus of this paper.

Stability studies to support early phase development

Early in development, pharmaceutical research organizations develop products with a primary focus on patient safety. Data are generated at appropriate storage conditions to demonstrate or support the stability of the drug substance and product to assure product quality through the clinical study period. Guidance documents are available to indicate the type of information needed to support clinical trials (3, 6–8). Although ICH stability guidelines outline the stability data needed to support storage conditions and shelf life for commercial submissions, these guidelines are not applicable to early stages of development when less is known about new drug substances and products (9). However, there must be appropriate data to support storage of the products being proposed for clinical use.

If a product is intended for human use, the concepts of cGMPs apply. For stability, this application often results in a written stability study plan or protocol, fit-for-purpose test methods, traceable and reliable documentation, and appropriate SOPs. Most compounds in early development end up being discontinued, for safety and/or efficacy issues and/or inadequate commercial viability. Therefore, efficiently assuring the quality of products being used in early human clinical trials is a challenge facing every pharmaceutical research organization involved in early trials. The common challenges faced in supporting drug substance (also referred to as API) and drug-product stability are discussed here. The authors offer some risk-based approaches for collecting data for small molecule, solid oral dosage forms used in Phase 1 and Phase 2a clinical trials, in hopes of guiding companies and health authorities towards harmonized strategies and best practices.

In early phase development, CMC requirements include generation of appropriate stability data at suitable storage conditions to support filing the IND (or IMPD/CTA) and use of the clinical material through the end of the clinical study. These scientific and regulatory objectives for stability must be met while at the same time minimizing nonvalue-added operational expenses. Several factors from a business, regulatory, and scientific perspective need to be taken into account when designing early phase development stability studies:

The risk tolerance of the sponsoring organization and their approach to the scientific mitigation of the risks.

The inherent stability of the drug substance or product, and prior product, process and stability knowledge.

The regulatory environment in the countries where the clinical trial will be conducted. For example, some countries may request stability data on multiple batches or actual clinical batches or may not accept extrapolation to justify use-date assignments.

The projected future use of the product. Development teams may have some idea of the likelihood that a project will continue into Phase 2b. If a product is expected to be used for many months or multiple years through several development phases, then a use-date extension proposal based on additional long-term data may be necessary and further knowledge gathering may be warranted (3). This information may influence the scope of the initial stability study in the form of additional time points, additional conditions, and/or additional tests.

Considering these factors, the industry must work to balance the perceived expectations of the regulators in the countries where clinical trials will be conducted using a science- and risk-based approach to generating and providing stability data in the regulatory filings.

Scope

Discussed in this article are recommendations with regard to generating stability data for drug substance and solid oral dosage forms used for Phase 1 and Phase 2a (early phases of development). This paper presents a framework and guiding principles to this end. The examples presented are not meant to be a "how to" guide, but rather illustrations of the principles being discussed. Other study designs and conditions may also be feasible with the appropriate justification.

The product development efforts for early clinical supplies often are simple formulations with limited development history. The early small-molecule oral products can be placed into one of two categories: drug-substance (DS) based products and formulated products. DS-based products include the use of neat DS (e.g., powder-in-bottle [PIB], powder-in-capsule (PIC), or DS shipped in bulk to clinical sites for on-site compounding). These products almost always have the same stability characteristics as the bulk DS, and DS stability data may be used to support the product use dating. Formulated products can be powders formulated with excipients, capsules filled with formulated granulation, or a tablet formulation. These formulations take more effort and are normally used because of a specific clinical need, a shortcoming of the DS-based product, or a desire to use the same formulation in Phases 1 and 2 studies. In most cases, they will be fairly simple formulations meant to have a short lifecycle. If the product advances further into development, more elegant formulations will need to be developed. Not covered in this paper are formulations that are extemporaneously prepared at the clinical site. These formulations are consumed quickly and long-term stability studies are not warranted.

In the following sections, DS and drug product (DP) stability considerations for early development are discussed.

Drug-substance stability

Representative drug-substance batches. A representative batch of DS, or DP, is one that is expected to have similar stability to the batches used in clinical production, based on a science- and risk-based assessment of attributes expected to influence stability and knowledge obtained during development. Often non-GMP or GLP (good laboratory practice) DS batches are manufactured first and placed on stability to support a variety of product development activities. These batches often are representative of GMP batches from a stability perspective and can be used to establish an initial retest period for the DS and support a clinical submission. Stability data included in the CMC section are limited at this stage of development (5). The DS batch used for Phase 1 clinical supply manufacture may be placed on stability concurrent to the clinical trials, if additional study is warranted.

In early development, it is common for the manufacturing process to be improved as a normal part of development. As the DS process evolves, an evaluation is needed to determine whether the initial batch placed on stability is still representative of the improved process. The authors advocate a science- and risk-based approach for deciding whether stability studies on new process batches are warranted. The basic principles are discussed below and further details of such an approach can be found in Ref. 10 and its citations (10).

The first step is to determine which DS attributes have an effect on stability. This step can be completed through paper-based risk assessments, prior knowledge, or through a head-to-head short-term stability challenge (as discussed in the next section) comparing the new batch with the earlier batch. If the revised process impacts one or more of these stability-related quality attributes, the new batch should be placed on stability. If the revised process does not result in a change to a stability-related quality attribute, the new batch does not need to be placed on stability. There are certain changes that almost always require a new study. Different polymorphic form, counter-ion, or solvate forms of a compound cannot be assumed to have the same rates of degradation or the same degradation pathways. Therefore, these changes will almost always require new stability data (11).

Typical changes encountered in early development include changes in synthetic pathway (including a change in the order of the bond forming steps), batch scale, manufacturing equipment or site, reagents, source materials, solvents used, and crystallization steps. In most cases, these changes will not result in changes in DS stability. A common misconception is that changes to the impurity profile will adversely affect stability. Most DS impurities, particularly organic impurities, are essentially inert and have no effect on DS stability. Some impurities, such as catalytic metals, acidic or basic inorganic impurities, or significant amounts of residual water or solvents, may affect stability, and if the new process changes the level of these impurities, additional stability may be warranted. Packaging changes of the bulk material to a less protective package may require stability data to support the change. Likewise, changing to a more protective package in order to extend the retest period, beyond what the original representative batch study could support, may require additional data in the new package.

Physical attributes that may impact stability include particle size/surface area, the degree of crystallinity/amorphicity, polymorphic form, hydrate form, and moisture content. If a new process changes any of these attributes, a risk assessment is recommended to determine whether additional stability is warranted. In some cases, short-term accelerated or stress stability data can help decide if these attributes are in fact stability related quality attributes. The concepts detailed in the above two paragraphs attempt to differentiate major and minor changes and may result in different stability strategies to support these changes.

A risk assessment may help to determine whether the current batch is sufficiently representative. Alternatively, additional data may be needed when the batch is not representative or when there is substantial doubt after the assessment.

Drug-substance stability data collection. Although the stability testing practices and the amount of collected data vary from company to company, three commonly used approaches are discussed here. One is that an early, representative DS batch is placed under real-time and accelerated conditions (e.g., 25 °C/60% RH and 40 °C/75% RH) and stability results for a few time points (e.g., 1–6 months) are generated to support an initial retest period (e.g., 12 months or more). If needed, the stability study can be continued to extend the retest period or the GMP material can simply be retested, as needed, as part of a retesting program commonly used for manufacturing components.

The selected analytical tests for stability studies should cover the quality attributes related to stability. Typically, these tests would include impurities and description and may include assay. Chiral purity, polymorphic form (e.g., x-ray), and water content should be tested, as appropriate. It may not be necessary to perform all tests at every time point depending on the purpose of the test.

A second approach is to use high stress conditions with a short time such as a high temperature and high humidity (HT/HH) model. For example, the DS is stored at 70 °C/75%RH in open and closed containers, while monitoring the chemical and physical stability up to three weeks. The chemical stability results are used to extrapolate the initial DS retest period up to 18 months, more or less if justified. The extrapolation is based on the principle of the classic Arrhenius relationship between temperature and the reaction (degradation) rate, assuming a pseudo-zero order reaction. It is a simple and fast prediction of DS stability (12). This approach is most applicable for DS that is considered to have good physical and chemical stability as demonstrated during drug discovery. Acceptance of this approach has been gained in a number of filings.

A third approach is the use of stress studies at several conditions coupled with modeling, such as the Accelerated Stability Assessment Program (ASAP) (13). ASAP combines an accelerated aging protocol with a humidity-corrected Arrhenius equation to provide an early prediction for DS and DP use period. It involves statistical analysis for more complex modeling of non-single order kinetics of degradation in DS and DP, and it produces faster and reliable predictions of chemical stability. For DS or DP with potential chemical stability challenges, this approach can be very useful to define appropriate storage condition and use period within a relatively short time to enable progressing early development programs. More importantly, ASAP has potential for a broader scope of stability assessment for developing control strategy of DP stability, such as long-term stability prediction and packaging requirements in implementing QbD for commercialization. ASAP has been used by companies as part of regulatory filings in multiple countries and has provided the basis for formulation, packaging, and moisture content justifications. There is an ongoing dialog between industry and regulatory agencies about these newer ways for industry to meet its obligations with respect to assuring the acceptability of products at the end of their shelf lives.

The knowledge gained from these studies can then be used to: support storage conditions and initial retest period assignments; design future stability studies; assess the impact of temperature excursions; and select packaging. The results can also be used to establish the initial use period for DS-based products (e.g., PIB or PIC). The accelerated or stress approaches may save time in arriving at a first estimate of a material's stability.

The retest period derived from these types of accelerated or stress studies can be later verified by placing the first clinical batch into real-time stability studies under ICH accelerated and long-term conditions. Future extensions of the retest/use period can be based on real-time data.

Assignment of retest date. Drug substance stability data, commensurate with the stage of development, can be generated to support use of the DS to manufacture clinical supplies through a system using retest dates. When a longer retest period is needed, the extensions are most commonly handled either through a stability program or through a batch-specific retest program. Wording may be provided in filings to outline how the retest period will be extended in the future. If using stability data from the second (HT/HH) or the third approach (ASAP), a retest period is extrapolated from the Arrhenius equation or moisture corrected Arrhenius equation (12). Stability testing also is used to support use period dating of simple DS-based products.

Design of drug-product stability studies for early development

Batch selection for stability studies. As noted earlier, early stage clinical supplies often are simple oral formulations or powder-in-bottle or powder-in-capsule. Stability studies at this early stage need to support the use of the product in the clinical studies and to facilitate further development. Unless a specific formulation is required for early phase studies (e.g., due to poor solubility, poor bioavailability, the need for once-a-day formulations, or the need for a sterile injectable formulation), a simple oral solid-dosage form is typically employed. For the DS in capsule or bottle, stability of the DS will support early stage development, however, the clinical supply may be placed on stability (e.g., retained samples) and tested, if necessary. The study would continue through completion of the clinical study and could also be monitored at later time points to increase product knowledge, if appropriate.

For formulated oral solid-dosage products, preformulation and process development studies can be performed to define the initial formulation. These studies will also provide initial stability information on the DS and its compatibility with excipients, moisture, processing conditions, and so forth. At this stage, a development batch (non-GMP) may be manufactured and placed on stability. If this batch is representative of the clinical supply (same or closely similar composition, process, and packaging) it can support the IND/IMPD filing and the initial use date for the product. If more than one strength is required, a bracketing stability design can be used. Changes to the clinical drug product need to be evaluated and additional batches placed on stability, as necessary. Using the same tools and thought processes that were mentioned in the DS portion of this paper, the first step is to determine what DP attributes have an effect on stability. If the new DP changes one or more of the stability-related quality attributes, the new batch should be placed on stability. Identification of these stability-related quality attributes can be facilitated through paper-based risk assessments, prior knowledge, or through short-term stability challenges. Changes that could impact product stability include major DS changes (e.g., solid form), formulation changes (e.g., drug to excipient ratio, different excipients), significant process changes (e.g., direct compression to wet granulation), and packaging changes (e.g., contact materials, blister versus bottle, change in size/headspace). Changes unlikely to affect stability for simple oral dosage forms include changes in scale, equipment, and site of manufacture.

Minimum requirements for a stability study to support early filings

Number of batches. Typically, there are limited batches in early development. Because these clinical studies are small, there is often a need for only one batch to be produced. For clinical materials expected to be used only through Phases 1 and 2a, the authors believe long-term data collected on the clinical batch or a batch representative of the clinical batch may be sufficient to ensure stability of the clinical product in early phase development. For stable products, additional batches of the same formulation do not need to be placed on stability.

Study duration and time points. Studies should generate data that give assurance that the clinical supplies retain their quality within acceptable limits at least through the use of the supplies in the clinic. Because early stage clinical studies can be relatively short, stability data need only support short-use periods. However, in many cases, extra samples are in reserve to extend studies for longer duration as a matter of practicality; for example, if the supplies are needed for longer duration than initial plans due to delays in the clinical program.

As noted, the ICH Q1A guideline on stability testing includes recommendations for stability studies for market application requirements but these are not meant to support early clinical trials. However, many of the ICH constructs are still useful such as the storage conditions and spacing of the time points. Spacing of the time points should be designed to capture the overall stability trend, noting that having a few earlier time points during screening studies or more formal stability studies to establish a use date by the time of filing can be desirable.

For DP, the early phase formulation usually will not be used in later clinical trials. As such, there is little value to carry the stability study beyond the time in the clinic.

The selected analytical tests for stability studies should cover the quality attributes that may change with time. Typically, these tests would include assay, impurities (i.e., degradation products), drug release (e.g., disintegration or dissolution), and description. If chiral conversion has been shown to be an issue in DS then it should be monitored in DP. It may not be necessary to perform all tests at every time point depending on the purpose of the test.

Data fromHT/HH stress studies may be useful in impact assessment for temperature excursions and to design efficient long-term studies. Another approach is the stress studies coupled with modeling, such as ASAP as discussed above. ASAP in some instances can give a good use period estimate in a shorter time than the traditional long-term stability approach. The use date derived from stress-extrapolation can be later verified by placing the first clinical batch into real-time stability studies under ICH accelerated and long term conditions.

Strategy for use dating and use-date extensions. Extrapolation of use periods is a commonly accepted practice and nearly a necessity in terms of getting clinical product packaged, labeled, released, and shipped to clinical sites with some use time remaining for storage at clinical sites. There has been much debate on how extrapolation of existing stability knowledge should be used to set use periods of clinical supplies. As was discussed at the beginning of this article, many factors will determine the amount of extrapolation that is defendable. Health authorities may be reluctant to accept extrapolations of more than 12 months past the existing long-term stability data, but it is possible to justify more or less extrapolation based on scientific grounds (see section on DS stability data collection). A one-size-fits-all approach is difficult to arrive at in terms of an exact number for allowed extrapolations, but an approach based on science and risk management is recommended.

With sufficient DS and drug product stability knowledge and a stable clinical formulation, the risk to the quality of the material is low when allowing for stability retest/use period extensions 12 months beyond available real-time stability data. This, however, would not be appropriate for an unstable drug product or one for which there is insufficient stability knowledge. This risk-based approach is based on three principles:

1) Stability attributes that limit shelf life are determined from early development studies and appropriate packaging and storage conditions selected.

2) Use-date assignments are monitored and confirmed though traditional (real time and accelerated) stability studies and appropriate actions taken if required.

It is worth stressing the point that stability data first included in regulatory filings are often just the beginning of a program to monitor the stability of the clinical supplies and continued monitoring to confirm storage claims and initial trends can be very useful for products that continue development.

The authors support the following recommendation from A. Kane: Companies often struggle with the strategy for updating retest/use period assignments throughout development and the consequent updates to the CMC submissions for IMPD and IMPD type dossiers. "Arguably the preference of many applicants would be to update assignments as more stability data are generated without the need for submission of a substantial amendment. To avoid the need for subsequent substantial amendments, the IMPD should contain the proposed specification and provide a clear explanation of how extrapolation is/will be applied to assign the retest/use period assignments" (14). It is the authors' belief that with a well-planned monitoring program, extrapolation with limited initial data is justified.

Conclusions

Demonstrating stability for clinical supplies should be driven by scientific knowledge gained in development as well a risk-based assessment to guide efficient use of available resources. In early development, clinical efforts are often focused on relatively simple products with short life cycles and the DS from which they are made are often produced by evolving chemical processes. The efforts to determine the stability of the DS and drug product should be fit for this phase of development and are designed to give the most basic stability information, namely, to ensure that the DS is of suitable quality when used to manufacture product and that the drug product is of suitable quality while in the clinic. To make this assessment, simple stability studies using ICH constructs and/or accelerated or stress data may be used. Other experimental data may be collected to increase the scientific knowledge of the DS/DP.

It is our hope that providing the approaches to early phase stability outlined here, along with the approaches in this series of white papers by the other focus areas of the IQ Early Phase GMPs working group, will provide a springboard to stimulate discussions on these approaches within the industry and with worldwide health authorities.

To encourage further dialogue, this IQ working group is planning a workshop in the near future to promote robust debate and discussion on these approaches. These discussions will hopefully provide improved alignment between development, QA oversight, and regulatory within the pharmaceutical industry, and most importantly with worldwide health authorities. Agreement between industry and health authorities regarding acceptable approaches to stability studies in early phases of drug development would clearly be beneficial to development scientists and allow for a more nimble and flexible approach to better address the dynamic environment typically encountered during the early phases of clinical development, while still providing appropriate controls to ensure patient safety.

Disclaimer

This article represents the opinion of the authors and not necessarily those of their respective companies.

Bruce Acken is in Analytical Sciences at Merck & Co. Inc. (Summit, NJ); Mark Alasandro is in Pharmaceutical Analysis and Microbiology at Allergan (Irvine, CA); Stephen Colgan is at Pfizer Global Research and Development (Groton CT); Paul Curry is in NCE Analytical R&D at Abbott Laboratories (Abbott Park, IL); Frank Diana is in Pharmaceutical Development at Endo Pharmaceuticals (Chadds Ford, PA); Q. Chan Li is in Analytical Development US, and Z. Jane Li is in Pharmaceutical Development, both at Boehringer Ingelheim Pharmaceuticals (Ridgefield, CT); Tony Mazzeo* is in Analytical and Bioanalytical Development at Bristol-Myers Squibb Company (New Brunswick, NJ); Andy Rignall is in Analytical Science at Astra Zeneca R&D (Macclesfield, UK); Z. Jessica Tan is in Analytical R&D at Amgen (Thousand Oaks, CA); and Robert Timpano is at Pfizer Global R&D (Groton, CT).